title: Dimethylfumarate induces apoptosis in human mast cells.
abstract: Mast cells modulate autoimmune diseases such as psoriasis and multiple sclerosis. Fumaric acid esters (FAEs) are widely used for the treatment of psoriasis, and dimethylfumarate (DMF) has recently been approved for multiple sclerosis. In this study, we analysed the cytotoxic effect of FAEs on human mast cells. Specifically, cell death was analysed in the human mast cell line HMC-1 and in primary cord blood-derived mast cells (CBMCs) after incubation with fumaric acid (FA), monomethylfumarate (MMF), DMF and calcium bis(monomethylfumarate) (Ca-MF). Our data show that only DMF potently induces apoptotic cell death in HMC-1 cells and CBMCs. DMF-mediated apoptosis was associated with increased expression of Bax and Bak and activation of caspase-9 and caspase-6. Interestingly, DMF also enhanced the sensitivity of CBMCs towards TRAIL- and dexamethasone-induced apoptosis. These findings demonstrate for the first time that DMF induces apoptosis of human mast cells, primarily via the mitochondrial apoptotic pathway. Our study contributes to the understanding of the beneficial effects of FAEs in autoimmune diseases and provides a rationale for exploiting FAEs for other diseases associated with mast cells.
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Förster
authors.forename: Liane M
authors.initials: LM
authors.lastname: Preussner
authors.forename: Jens M
authors.initials: JM
authors.lastname: Seeger
authors.forename: Anja
authors.initials: A
authors.lastname: Rabenhorst
authors.forename: Hamid
authors.initials: H
authors.lastname: Kashkar
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mrowietz
authors.forename: Karin
authors.initials: K
authors.lastname: Hartmann
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000737:chemistry; D053178:Caspase 6 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D003879:Dermatologic Agents / Q000737:chemistry*; D003907:Dexamethasone / Q000737:chemistry; D000069462:Dimethyl Fumarate; D005047:Etoposide / Q000737:chemistry; D005650:Fumarates / Q000737:chemistry*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008298:Maleates / Q000737:chemistry; D008407:Mast Cells / Q000187:drug effects*; D008727:Methotrexate / Q000737:chemistry; D011565:Psoriasis / Q000473:pathology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494772:BAK1 protein, human; C494826:BAX protein, human; C508606:CXCL8 protein, human; D003879:Dermatologic Agents; D005650:Fumarates; D016209:Interleukin-8; D008298:Maleates; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C073341:citraconic acid; D005047:Etoposide; D003907:Dexamethasone; C505514:CASP6 protein, human; C506433:CASP9 protein, human; D053178:Caspase 6; D053453:Caspase 9; D000069462:Dimethyl Fumarate; D002118:Calcium; D008727:Methotrexate
keywords: apoptosis; dimethylfumarate; fumaric acid esters; mast cells; psoriasis